Is Valproic Acid Ototoxic?

7 A forum for case studies, clinical notes and observations, and other clinical material that does not have a traditional research format. V alproic acid (VPA), or valproate, was first discovered in 1882 by Burton, but its anticonvulsant properties were not Although thousands of patients have been treated with VPA, only recently has the question of VPA ototoxicity been raised. The first reports described possible changes in auditory brainstem response (ABR) peak latencies (Medaglini et al. (1990) reported hearing loss for two patients attaining very high blood levels of VPA (200 and 300 µg/ml). (The usual " therapeutic range in our laboratory is 50–120 µg/ml although it may be lower for add-on therapy.) Although baseline audiometrics were not obtained in the Armon et al. 1990 study, the patients' auditory thresholds appeared to improve after termination of VPA therapy. However, several problems existed in the study methods. First, audiologic procedures, equipment, and qualifications of the individuals performing the tests were not specified. Second, only air-conduction thresholds were obtained; therefore, any change in hearing threshold could have been either conductive or sensorineural. Generally, only sensorineural changes are considered to be the result of ototoxicity. Third, the initial audio-logic testing was performed while the patients were experiencing severe atypical adverse reactions to VPA including severe action tremor, weight loss exceeding ten pounds, memory and cognition problems, nausea, insomnia, irritability, and unpredictable behavior, among other difficulties. Audiometric thresholds reportedly improved after discon-tinuation of VPA and the other symptoms subsided. The authors did not discuss the possibility that very ill or disoriented patients may yield unreliable audiometric threshold data. When a patient's physical and mental states improve, frequently more reliable data may be obtained. Another consideration is that neither the study patients nor the reactions to VPA were typical. Both patients received very high dosages of VPA and had neurologic problems other than epilepsy including stroke, meningitis, resection of arteriovenous malformation (AVM), and the Janetta procedure for hemifa-cial spasm. Additionally, both patients were elderly (68 and 72 years) and had Parkinson's disease. Although a postscript in the paper mentioned a third patient, specifics were not provided. It should be emphasized that the VPA levels in these patients (200–300 µg/ml) are far above the usual therapeutic range and any changes in these patients may have reflected those toxic levels. Based on a telephone survey, Armon et al. (1991) reported that 16 of 38 VPA patients (42%) …